Inhibitory interneurons play a number of key roles in normal neocortical function. For example, they shape sensory receptive fields and drive high frequency gamma oscillations. On the other hand, defects in their function can lead to seizures. We have examined the properties of two major functional interneuronal subclasses: fast spiking (FS) and low-threshold spike firing (ITS) neurons of rat neocortical layer V. Data indicate that each group expresses a novel form of self inhibition, namely autaptic inhibitory responses in FS cells and an endocannabinoid-mediated slow self-inhibition in ITS interneurons. We will address two major questions relevant to self-inhibition of neocortical interneurons: 1) What are the roles of FS cell autapses in regulating precision of spike timing and in coordinating fast network synchrony? 2) What are the mechanisms leading to long-lasting inhibition in ITS neurons, and the physiological conditions necessary for its induction? Overall these two experimental aims will address the central themes of this grant, the mechanisms that modulate and control neocortical interneuronal activities and the functional consequences of such modulation on neocortical circuit function. Experimental approaches will include: single and paired whole cell voltage- and current-clamp recordings and perforated-patch recordings from visualized interneurons in rat neocortical slices; intracellular labeling with biocytin; intracellular and extracellular application of ions and pharmaceutical agents to affect transmitter release and receptor function; and use of dynamic clamp. Results will lead to a better understanding of synaptic modulation of two major subclasses of neocortical interneurons and provide information regarding GABAergic regulation of neocortical excitability relevant to both normal and pathophysiological cortical function.